Abstract

Background

Overall survival (OS) is considered the gold standard for clinical benefit in oncology trials, but mature data are often unavailable. A relationship between progression-free survival (PFS) and OS in advanced cancer, including breast cancer (BC), is known: FDA (2007) suggests PFS may be a surrogate for OS; a NICE DSU report (Davis et al 2012) presents evidence of a relationship between PFS and OS in BC. This analysis further examined the relationship between PFS and OS with a view of using PFS as a predictor of OS using data from the Phase II FIRST study (n = 205; NCT00274469) of fulvestrant 500 mg vs. anastrozole as first-line treatment in hormone-receptor positive advanced BC.

Methods

In the interests of homogeneity, the relationship between PFS and OS was evaluated in endocrine-naïve patients in the FIRST study (n = 73 [72%] fulvestrant; n = 80 [78%] anastrozole) by substituting the linear expression into each other and using Weibull parametric fits and linear regression. PFS and OS data from a study of anastrozole in a similar population (Nabholtz et al 2000, 2003) were applied to validate the Weibull and linear regression model.

Results

Using log cumulative hazard plots, a linear trend was shown for PFS and OS. From the Weibull model, relationships between OS and PFS were derived: for given S, number surviving, fulvestrant ln time_OS(S) = 0.82 + 0.80 ln time_PFS(S); and anastrozole ln time_OS(S) = 0.97 + 0.79 ln time_PFS(S). Based on linear regression of part of the PFS and OS curve (driven by apparent deviation from a linear relationship), the following relationships were derived: fulvestrant ln time_OS(S) = 0.77 + 0.63 ln time_PFS(S); and anastrozole ln time_OS(S) = 0.95 + 0.67 ln time_PFS(S). In all equations, time = days/1000. Applying both models to other clinical data for anastrozole showed a good fit and thus extends this relationship beyond the FIRST study.

Conclusions

This analysis shows a novel, validated approach by which the relationship between PFS and OS in patients receiving first-line treatment with fulvestrant or anastrozole can be modelled. These results add to the acceptance of PFS as a predictor of OS in this setting.